Proteomic characterization of hippocampus of chronically socially isolated rats treated with fluoxetine: Depression-like behaviour and fluoxetine mechanism of action

• Published in: Neuropharmacology 2018-06, Vol.135, p.268-283
• Main Authors: Perić, Ivana, Costina, Victor, Stanisavljević, Andrijana, Findeisen, Peter, Filipović, Dragana
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Depression - metabolism; Depression - prevention & control; Depression - psychology; Depressive disorder; Fluoxetine; Fluoxetine - pharmacology; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Male; Mitochondria - metabolism; Protein interactomics; Proteome - drug effects; Proteome - metabolism; Proteomics; Quantitative proteomics; Rats; Social Isolation - psychology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2018.03.034

Due to the severity of depressive symptoms, there remains a necessity in defining the underlying mechanisms of depression and the precise actions of antidepressants in alleviating these symptoms. Proteomics is a powerful and promising tool for discovering novel pathways of cellular responses to disease and treatment. As chronic social isolation (CSIS) is a valuable animal model for studying depression, we performed a comparative subproteomic study of rat hippocampus to explore the effect of six weeks of CSIS and the therapeutic effect of chronic fluoxetine (Flx) treatment (last three weeks of CSIS; 15 mg/kg/day). Behaviorally, Flx treatment normalized the decreased sucrose preference and increased marble burying results resulting from CSIS, indicative of a FLX-induced attenuation of both anhedonia and anxiety. An analysis of cytosolic and nonsynaptic mitochondrial subproteome patterns revealed that CSIS resulted in down-regulation of proteins involved in mitochondrial transport and energy processes, primarily tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Chronic Flx treatment resulted in an up-regulation of CSIS-altered proteins and additional expression of other transporter and energy-involved proteins. Immunohistochemical analysis revealed hippocampal subregion-specific effects of CSIS and/or Flx treatment on selective protein expressions. [Display omitted] •Fluoxetine reversed depressive- and anxiety-like behaviours induced by CSIS.•CSIS deregulated the expression of mitochondrial transport-involved proteins.•CSIS deregulated transmembrane transport and oxidative phosphorylation.•Fluoxetine reversed the effect of CSIS on mitochondrial transport.•Fluoxetine stimulated main mitochondrial energy processes.